J William Deaver, Patrick J Ryan, Colleen L O'Reilly, Selina Uranga, Sara Mata López, Melinda Sheffield-Moore, Peter P Nghiem, Steven E Riechman, James D Fluckey
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引用次数: 0
Abstract
The hyperactivation of mTOR is a significant contributor to the development and progression of a number of human diseases, including a majority of human cancers. Although there have been many scientific and clinical efforts to reduce the impact of mTOR hyperactivation on downstream cellular metabolism, we aimed to mitigate this hyperactivation through a novel targeted gene edit of the intrinsic mTOR inhibitor, DEP domain containing MTOR interacting protein (DEPTOR), in MCF7 human breast cancer cells. Using publicly available bioinformatics tools, we demonstrate that DEPTOR gene expression is low in breast cancers compared with healthy tissues and that DEPTOR expression predicts overall survival, recurrence-free survival, and distant metastasis-free survival in breast cancer patients. We show that a directed overexpression of DEPTOR protein leads to significant alteration of downstream mTORC1 targets and subsequently reduces overall rates of protein synthesis. In addition, treatment of DEPTOR overexpressing cells with small-molecule DEPTOR inhibitor NSC126405 leads to a reversal of this effect, indicating a direct causal mechanism between DEPTOR protein levels and mTORC1 activation.NEW & NOTEWORTHY We identify DEPTOR as a predictor of mortality in breast cancer and show that precision gene editing to restore DEPTOR expression in breast cancer slows cell growth by inhibiting mTOR activity.
期刊介绍:
The American Journal of Physiology-Cell Physiology is dedicated to innovative approaches to the study of cell and molecular physiology. Contributions that use cellular and molecular approaches to shed light on mechanisms of physiological control at higher levels of organization also appear regularly. Manuscripts dealing with the structure and function of cell membranes, contractile systems, cellular organelles, and membrane channels, transporters, and pumps are encouraged. Studies dealing with integrated regulation of cellular function, including mechanisms of signal transduction, development, gene expression, cell-to-cell interactions, and the cell physiology of pathophysiological states, are also eagerly sought. Interdisciplinary studies that apply the approaches of biochemistry, biophysics, molecular biology, morphology, and immunology to the determination of new principles in cell physiology are especially welcome.